The major function of the epidermis is to provide a barrier between the external environment and the organism To fulfill this function keratinocytes undergo a complex pathway of differentiation which culminates in cornification and the formation of extracellular lipid enriched membranes in the stratum corneum (SC). The regulation of this process is not well understood but lipophilic compounds, such as retinoids and vitamin D, which interact with nuclear hormone receptors play an important role. We have recently shown that activation of PPARalpha, a member of the nuclear hormone receptor family, regulates keratinocyte differentiation. We have shown 1) that PPARalpha ligands accelerates the development of the extracellular lipid enriched membranes in the SC of fetal rats, 2) that PPARalpha ligands increase the activity in fetal epidermis of two lipid metabolic enzymes essential for formation and function of the SC. beta- glucocerebrosidase, and steroid sulfatase, 3) that PPARalpha ligands increase filaggrin and loricrin mRNA and protein expression in fetal epidermis and 4) that PPARalpha ligands increase mRNA and protein levels of involucrin and transglutaminase 1 in human keratinocytes in culture. These results demonstrate that treatment with PPARalpha ligands affects several key components of terminal differentiation. Hypothesis: That PPARalpha ligands stimulate keratinocyte/epidermal differentiation. Aim 1: To determine in human keratinocytes in culture if PPARalpha ligands induce the expression of structural proteins important for keratinocyte differentiation and determine the mechanisms for this increase. Aim 3: Using PPARalpha Knockout mice determine the importance of PPARalpha in regulating the expression of structural proteins and lipid enzymes in culture mouse keratinocytes and in intact epidermis.